JP2009513633A - Combination of dipeptidyl peptidase-4 inhibitor and antihypertensive agent for the treatment of diabetes and hypertension - Google Patents

Abstract

  The present invention relates to a pharmaceutical composition comprising a combination of a specific dipeptidyl peptidase-4 (DPP-4) inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor, such as Kits comprising the combination and methods of using such compositions to treat diabetes, diabetes related disorders, hypertension and hypertension related disorders.

Description

  The present invention relates to a pharmaceutical composition comprising a combination of a specific dipeptidyl peptidase-4 (DPP-4) inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme (ACE), Kits comprising such combinations, methods of using such compositions to treat diabetes, diabetes associated with hypertension, diabetes related disorders, hypertension and hypertension related disorders.

  Diabetes mellitus is caused by a number of factors and is most simply characterized by high plasma glucose levels (hyperglycemia) in the fasting and post-glucose state. Diabetes is generally recognized in two forms: type 1 diabetes or insulin-dependent diabetes mellitus (IDDM), where the patient secretes little or no insulin, a hormone that regulates glucose utilization, and patients receive insulin. There is type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM) that is secreted to some extent and may show hyperinsulinemia (similar or higher plasma insulin levels compared to non-diabetic patients) but at the same time hyperglycemia . Type 1 diabetes is typically treated with exogenous insulin administered by injection. However, type 2 diabetes often develops "insulin resistance" and reduces the effectiveness of insulin in stimulating glucose and lipid metabolism in key insulin sensitive tissues such as muscle, liver and adipose tissue. Patients who are insulin resistant but not diabetic do not have elevated serum glucose levels because they have high insulin levels that compensate for their insulin resistance. Type 2 diabetic patients are hyperglycemic because they cannot sufficiently overcome significant insulin resistance even at high plasma insulin levels.

  Insulin resistance is primarily due to a post-receptor signaling defect that has not yet been fully elucidated. Insulin resistance results in inactive glucose ingestion, glucose oxidation and decreased glycogen accumulation in muscle, lack of inhibition of adipose tissue lipolysis by insulin, inappropriate suppression of glucose production by the liver, etc. .

  Persistent or uncontrolled hyperglycemia that occurs in diabetes leads to increased morbidity and youth morbidity. Type 2 diabetes is at high risk of concurrent cardiovascular complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, kidney damage, neuropathy and retinal damage.

Many patients who have insulin resistance but have not yet developed type 2 diabetes are also at risk of developing a metabolic syndrome, also called X syndrome, insulin resistance syndrome, or pullimetabolic syndrome. During the period of 5 to 10 years before onset of impaired glucose tolerance, several hormonal imbalances have occurred, which cause increased visceral fat mass, hypertension, insulin resistance and hyperlipidemia (Bjornstop, P., Current Topics in Diabetes Research , eds. Belfore, F., Bergman, RN, and Molinath, GM, Front Diabetes, Basel, Karger, 12: 182-192 (1993). Similarly, metabolic syndrome is characterized by insulin resistance coexisting with abdominal obesity, hyperinsulinemia, hypertension, low HDL, high VLDL. Although causal relationships between the various components of metabolic syndrome have not yet been confirmed, insulin resistance or abdominal obesity is thought to play an important role (Requen, GM et al., N. Eng . J. Med) . , 334: 374-381 (1996); Despres, JP et al., N. Engl . J. Med ., 334: 952-957 (1996); Wajchenberg, BL, Diabetes / Metabolism Rev. , 10: 19-29 (1994)). Patients with metabolic syndrome are at increased risk of developing the cardiovascular complications listed above, whether or not they have manifested diabetes mellitus. Diabetes can be treated with a variety of therapeutic agents, including insulin sensitizers, including, for example, PPARγ agonists such as glitazone and glitazar; biguanides; protein tyrosine phosphatase 1B inhibitors; dipeptidyl peptidase-4 inhibitors; insulin Insulin mimetics; sulfonylureas; meglitinides; α-glucosidase inhibitors; and α-amylase inhibitors.

  Increased plasma insulin levels obtained by administration of sulfonylureas (eg tolbutamide and glipitide) or meglitinide that stimulate pancreatic β-cells to increase insulin secretion and / or by insulin injection when sulfonylurea or meglitinide is ineffective Can provide a sufficiently high insulin concentration to stimulate insulin resistant tissue. However, plasma glucose levels can be dangerously reduced or insulin resistance can be increased due to elevated plasma insulin levels. Biguanide, whose mechanism of action is unknown, reduces hepatic glucose output, improves insulin sensitivity, and corrects hyperglycemia to some extent. Metformin monotherapy is often used to treat patients with type 2 diabetes complicated by obesity and / or dyslipidemia. When there is no proper response to metformin, treatment with sulfonylurea, thiazolidinedione, insulin or α-glucosidase inhibitors is often continued. However, the two biguanides, phenformin and metformin, also induce lactic acidosis and vomiting / diarrhea, respectively. Α-Glucosidase inhibitors such as acarbose act by delaying glucose absorption in the intestine. Alpha-amylase inhibitors inhibit the enzymatic degradation of starch or glycogen into maltose and reduce the amount of sugar available to the body.

  PPAR-γ agonists, including glitazones, also known as thiazolidinediones (ie 5-benzylthiazolidine-2,4-diones), and non-thiazolidinediones or glitazars can alleviate many symptoms of type 2 diabetes Represents another class of compounds with sex. These agents substantially improve muscle, liver and adipose tissue insulin sensitivity in some type 2 diabetes animal models, resulting in partial or elevated plasma glucose levels without developing hypoglycemia Completely correct. Commonly marketed glitazones are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. It is generally believed that one cause of the improved insulin sensitivity observed with glitazone is PPAR-gamma agonism. Newer PPAR agonists being developed for the treatment of type 2 diabetes and / or dyslipidemia are one or more agonists of the PPAR alpha, gamma and delta subtypes.

However, treatment of diabetes with PPARγ agonists was accompanied by fluid retention. The revised new label for the PPARγ agonist Avandia® ⁽ rosiglitazone maleate ⁾ suggests to patients that there is a risk of fluid accumulation and volume related events such as edema and congestive heart failure.

  Treatment of type 2 diabetes also typically includes physical exercise, weight control and diet. Although physical exercise and reduced dietary caloric intake will dramatically improve the diabetic state, this treatment method is extremely compliant because of the sedentary lifestyle and especially the excessive consumption of highly saturated fat foods. hard. In any case, weight loss and exercise gain are difficult for most diabetics. There is a continuing need for new methods of treating and preventing diabetes-related disorders such as diabetes, hypertension-associated diabetes, and metabolic syndrome. At present, there is no established treatment method for metabolic syndrome.

  The present invention comprises specific dipeptidyl peptidase-4 (DPP-4) inhibitors, angiotensin II receptor antagonists and ACE inhibitors for the treatment of diabetes, hypertension-associated diabetes, diabetes-related disorders, hypertension, hypertension-related disorders This problem is solved by proposing a combination therapy that includes a group or selected antihypertensive drug. Combinations of these drugs at each clinical dose are expected to be more effective than treatment with one drug alone. Such sub-clinical doses are expected to produce clinical effects with fewer side effects than monotherapy using one drug at a clinical dose. As a result, the combination therapy is expected to achieve a desired medical effect without the problem of trial and error associated with the individual prescription of each drug in the initial medical treatment.

SUMMARY OF THE INVENTION The present invention provides a composition comprising an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor, and in particular an antidiabetic agent that is a DPP-4 inhibitor. The composition is useful for the treatment, management and / or prevention of diabetes, hypertension associated diabetes, diabetes related disorders, hypertension and hypertension related disorders.

The therapeutic efficacy of DPP-4 inhibitors for the treatment of type 2 diabetes is (i) J. et al. Drucker in Exp. Opin. Invest. Drugs , 12: 87-100 (2003); Augustyns et al., In Exp. Opin. Ther. Patents , 13: 499-510 (2003); (iii) C.I. F. Deacon et al . In Exp. Opin. Investig. Drugs , 13: 1091-1102 (2004); (iv) A.A. E. Weber, “Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Diabetes,” J. Med. Chem . 47: 4135-4141 (2004); and (v) J. MoI. J. et al. Hoist, “Treatment of Type 2 diabetics with agents of the GLP-I receptor or DPP-4 inhibitors,” Exp. Opin. Emerg. Drugs , 9: 155-166 (2004).

  The compositions of the present invention are useful for the treatment, management and / or prevention of human diabetes, particularly type 2 diabetes.

  The compositions of the present invention further comprise hyperlipidemia; dyslipidemia; obesity; abdominal obesity; hypercholesterolemia; hypertriglyceridemia; atherosclerosis; coronary heart disease; Peripheral vascular disease; vascular recurrent stenosis; renal disorder; neuropathy; inflammatory conditions, including but not limited to inflammatory bowel diseases such as inflammatory bowel syndrome, Crohn's disease and ulcerative colitis; other inflammatory conditions; pancreatitis Neurodegenerative disease; retinal disorders; neoplastic conditions, including but not limited to adipocyte tumors such as adipocyte tumors, liposarcomas; cancers including gastric cancer and bladder cancer; angiogenesis; Alzheimer's disease; psoriasis; and insulin resistance Useful for the treatment, management and / or prevention of other disorders where gender is a component.

  Compositions of the present invention also include overeating; bulimia; high plasma insulin levels; insulin resistance; glucose tolerance; lipid disorders; low HDL levels; high LDL levels; hyperlipidemia; endometrial cancer, breast cancer, prostate cancer , Neoplastic conditions such as renal and colon cancer; osteoarthritis; obstructive sleep apnea; gallstones; abnormal heart rate; cardiac arrhythmia; myocardial infarction; congestive heart failure; Syndrome); craniopharyngioma; Prader-Willi syndrome; Frehrig syndrome; GH-deficient patient; normal mutant short stature; Turner syndrome; and reduced metabolic activity and, for example, children with acute lymphoblastic leukemia Useful for the treatment, management and / or prevention of other pathological conditions that show a reduction in resting energy expenditure expressed as a percentage of total fat free weight.

  The compositions of the present invention are also useful for treating, managing and / or preventing diabetes while reducing cardiac hypertrophy, such as left ventricular hypertrophy.

  The compositions of the present invention are further useful for the treatment, management and / or prevention of metabolic syndrome.

  The invention also relates to the treatment of these conditions and the use of the compositions of the invention for the manufacture of a medicament useful for the treatment of these conditions.

  The present invention also relates to a pharmaceutical composition comprising a specific DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor as a pharmaceutically active ingredient.

  The present invention is also selected from the group consisting of a specific DPP-4 inhibitor, an angiotensin II receptor antagonist and an ACE inhibitor for the manufacture of a medicament for the treatment of diabetes, hypertension associated diabetes, diabetes related disorders, hypertension and hypertension related disorders Related to use with antihypertensive drugs. The medicament comprises a therapeutically effective amount of such a DPP-4 inhibitor and such an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor in a combined or individual form.

  The present invention also provides a specific DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor for diabetes, hypertension associated diabetes, diabetes related disorders, hypertension and hypertension related disorders simultaneously. Relates to a pharmaceutical comprising as a combined preparation for individual or sequential use.

  The present invention also provides diabetes, hypertension-associated diabetes, diabetes-related disorders, hypertension by combining specific DPP-4 inhibitors that can be administered individually with an antihypertensive agent selected from the group consisting of angiotensin II receptor antagonists and ACE inhibitors. And relates to the treatment of hypertension related disorders.

  The invention also relates to merging individual pharmaceutical combinations into one kit form.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antihypertensive agent selected from the group consisting of angiotensin II receptor antagonists and ACE inhibitors useful for the treatment or prevention of diabetes, hypertension associated diabetes, diabetes related disorders, hypertension and hypertension related disorders. A composition comprising a specific DPP-4 inhibitor and an antidiabetic agent.

  The antihypertensive agent used in the composition of the present invention is selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor.

  In one embodiment, the antihypertensive agent is an angiotensin II receptor antagonist. Preferably the angiotensin II receptor antagonist is selected from the group consisting of losartan, candesartan, irbesartan, valsartan, telmisartan and eprosartan, all their stereoisomers, pharmaceutically acceptable salts, hydrates and crystalline forms Is done. U.S. Pat. No. 5,136,069 conceptually and specifically describes 2-butyl-4-chloro-1- [p- (o-1H-tetrazol-5-ylphenyl) -benzyl] imidazole-5-methanol potassium. Salt (Losartan potassium) and anhydrous form of 2-butyl-4-chloro-1-[(2 ′-(1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] -imidazole-5-carboxylic acid The hydrochloride salt of is described. 2-Butyl-4-chloro-1-[(2 ′-(1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] imidazole-5-carboxylic acid is 2-butyl-4-chloro- It is an active metabolite of 1- [p- (o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-methanol potassium salt. US Pat. No. 5,136,069, columns 261-263 describes general compounding procedures for the compounds described in that patent, including capsules, tablets, injection formulations and suspensions. US Pat. No. 5,153,197 describes the use of these compounds alone and in combination with diuretics to treat hypertensive patients. US Pat. No. 5,310,929 describes 5-imidazole carboxyl ester angiotensin II receptor antagonist prodrugs. Losartan potassium is preferred.

  In another embodiment, the antihypertensive agent is an ACE inhibitor. Preferably, the ACE inhibitor is alacepril, benazepril, captopril, celonapril, cilazapril, delapril, enalapril, enalapril, fosinopril, imidapril, lisinopril, mobiletipril, moexipril, perindopril, quinapril, prampril, prampril, prampril Selected from the group consisting of stereoisomers, pharmaceutically acceptable salts, hydrates and crystalline forms.

  In some cases, the following antihypertensive drugs can also be used. Neutral endopeptidase inhibitors (eg, thiorphan and phosphoramidon), aldosterone antagonists, renin inhibitors (eg, urea derivatives of di- and tri-peptides (see: US Pat. No. 5,116,835), amino acids and derivatives (US patents) 5,095,119 and 5,104,869), amino acid chains linked by non-peptide bonds (US Pat. No. 5,114,937), di- and tri-peptide derivatives (US Pat. No. 5,106,835), peptidyl Aminodiol (US Pat. Nos. 5,063,208 and 4,845,079) and peptidyl beta-aminoacylaminodiol carbamate (US Pat. No. 5,089,471); also US Pat. Nos. 5,071,837; 5,064,965 ; 5 63,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, various other peptide analogs, small molecule renin inhibitors (eg, diols) Sulfonamides and sulfinyls (US Pat. No. 5,098,924), N-morpholino derivatives (US Pat. No. 5,055,466), N-heterocyclic alcohols (US Pat. No. 4,885,292) and pyroimidazolone (US Pat.) Also pepstatin derivatives (US Pat. No. 4,980,283) and fluoro- and chloro-derivatives of statatone-containing peptides (US Pat. No. 5,066,643), Enalcrane, RO42-5892, A65317, CP80794, ES1005, ES8891 SQ34017, aliskiren (2 (S) 4 (S), 5 (S), 7 (S) -N- (2-carbamoyl-2-methylpropyl) -5-amino-4-hydroxy-2,7-diisopropyl-8- [4-methoxy-3 -(3-methoxypropoxy) phenyl] -octanamide hemifumarate), SPP600, SPP630 and SPP635), endothelin receptor antagonists, vasodilators, calcium channel blockers (eg amlodipine, nifedipine, verapamil, diltiazem, galopamil, Nildipine, nimodipine, nicardipine), potassium channel activators (eg, nicorandil, pinacidil, cromakalim, minoxidil, apricalim, loprazolam), diuretics (eg, hydrochlorothiazide), sympathetic blockers, beta-adrenali Blockers (eg, propranolol, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol tartrate), alpha-adrenergic blockers (eg, doxazosin, prazosin or alphamethyldopa), central alpha adrenergic agonists, peripheral vasodilators (eg, Hydralazine).

  Alternatively, the present invention is useful for the treatment or prevention of diabetes, hypertension-associated diabetes, diabetes-related disorders, hypertension, hypertension-related disorders, including an antihypertensive agent that is a renin inhibitor and an antidiabetic agent that is a specific DPP-4 inhibitor. A composition is provided. Since a renin inhibitor is a compound that inhibits the renin-angiotensin renin enzyme, it is a therapeutically effective compound for treating hypertension. Such compounds include, but are not limited to, di- and tri-peptide urea derivatives (see: US Pat. No. 5,116,835), amino acids and derivatives (US Pat. Nos. 5,095,119 and 5,104,869). ), Amino acid chains linked by non-peptide bonds (US Pat. No. 5,114,937), di- and tri-peptide derivatives (US Pat. No. 5,106,835), peptidylaminodiol (US Pat. No. 5,063,208 and 4,845,079) and peptidyl beta-aminoacylaminodiol carbamate (US Pat. No. 5,089,471); also US Pat. No. 5,071,837; 5,064,965; 5,063,207; 054; 5,036,053; 5,034,512 and 4,894,437. Peptide analogs such as: small molecule renin inhibitors (diol sulfonamides and sulfinyl (US Pat. No. 5,098,924), N-morpholino derivatives (US Pat. No. 5,055,466), N-heterocyclic alcohols (US Pat. 885,292) and pyroimidazolone (US patent); pepstatin derivatives (US Pat. No. 4,980,283); fluoro- and chloro-derivatives of statatone-containing peptides (US Pat. No. 5,066,643); 5892, A65317, CP80794, ES1005, ES8891, SQ34017, aliskiren (2 (S), 4 (S), 5 (S), 7 (S) -N- (2-carbamoyl-2-methylpropyl) -5-amino -4-Hydroxy-2,7-diisopropyl-8- [4- Butoxy-3- (3-methoxypropoxy) phenyl] - oct cyanamide hemifumarate), including SPP600, SPP630 and SPP635.

  The methods and compositions of the invention also include

から成るグループから選択される特定のＤＰＰ−４インヒビターならびに医薬的に許容されるその塩、水和物および結晶質形態の抗糖尿病薬を含む。

Specific DPP-4 inhibitors selected from the group consisting of and pharmaceutically acceptable salts, hydrates and crystalline forms of antidiabetic agents.

  In one embodiment, the particular DPP-4 inhibitor has the structural formula IV:

の（２Ｒ）−４−オキソ−４−［３−（トリフルオロメチル）−５，６−ジヒドロ［１，２，４］トリアゾロ［４，３−α］ピラジン−７（８Ｈ）−イル］−１−（２，４，５−トリフルオロフェニル）ブタン−２−アミンまたは医薬的に許容されるその塩、水和物もしくは結晶質形態である。

(2R) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl]- 1- (2,4,5-trifluorophenyl) butan-2-amine or a pharmaceutically acceptable salt, hydrate or crystalline form thereof.

  In one class of this embodiment, the pharmaceutically acceptable salt of the compound of formula IV is structural formula V:

のリン酸二水素塩または医薬的に許容されるその水和物である。このクラスの１つのサブクラスでは、医薬的に許容される水和物が結晶質一水和物である。結晶質のリン酸二水素一水和物をリン酸シタグリプチンと呼ぶ。

Of dihydrogen phosphate or a pharmaceutically acceptable hydrate thereof. In one subclass of this class, the pharmaceutically acceptable hydrate is crystalline monohydrate. Crystalline dihydrogen phosphate monohydrate is called sitagliptin phosphate.

DPP-4 inhibitors in the compositions of the present invention are disclosed in US Pat. No. 6,699,871. The entire contents of the patent are incorporated herein by reference. The development of this series of DPP-4 inhibitors is described in D.C. Kim et al . Med. Chem . 48: 141-151 (2005).

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) the treatment, management or treatment of diabetes, particularly non-insulin dependent diabetes mellitus, comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof. It relates to prevention methods.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) relates to a method for treating, managing or preventing hypertension associated diabetes comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) hypercholesterolemia, atherosclerosis, low HDL levels comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof. Relates to a method for treating, managing or preventing high LDL levels, hyperlipidemia, hypertriglyceridemia and / or dyslipidemia.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) It relates to a method for treating, managing or preventing hyperglycemia, comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) It relates to a method for treating, managing or preventing hypercholesterolemia comprising the step of administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) relates to a method for the treatment, management or prevention of hypertriglyceridemia comprising the step of administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof, lipid disorders, hyperlipidemia, dyslipidemia, high The present invention relates to a method for treating, managing or preventing non-HDL cholesterol and low-HDL cholesterol.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) treating, managing or treating dyslipidemia, including low HDL cholesterol, comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof. It relates to prevention methods.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) relates to a method for treating, managing or preventing atherosclerosis comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

  It will be appreciated that this treats the aftereffects of atherosclerosis (stenosis, lameness, heart attack, stroke, etc.).

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) treating diabetes while reducing cardiac hypertrophy, particularly left ventricular hypertrophy, comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof. , How to manage or prevent.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) It relates to a method for treating, managing or preventing metabolic syndrome comprising the step of administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) relates to a method for treating a diabetes-related disorder comprising administering a therapeutically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) It relates to a method for treating or preventing hypertension, comprising administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

The present invention also provides for patients in need thereof:
(A) a therapeutically or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof;
(B) relates to a method for the treatment or prevention of hypertension-related disorders comprising the step of administering a therapeutically or prophylactically effective amount of a specific DPP-4 inhibitor or a pharmaceutically acceptable salt thereof.

  The present invention also relates to pharmaceutical compositions and medicaments useful for performing these methods.

  The present invention is selected from the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof for the manufacture of a medicament for the treatment, management or prevention of diabetes It relates to the use of antihypertensive drugs and certain DPP-4 inhibitors or antidiabetic drugs which are pharmaceutically acceptable salts, hydrates or crystalline forms thereof. The medicament comprises an effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The present invention also includes an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof for the manufacture of a medicament for the treatment, management or prevention of hypertension-associated diabetes. It relates to the use of selected antihypertensive drugs and specific DPP-4 inhibitors or antidiabetic drugs which are pharmaceutically acceptable salts, hydrates or crystalline forms thereof. The medicament comprises a therapeutically or prophylactically effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The present invention also relates to the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof for the manufacture of a medicament for the treatment, management or prevention of diabetes related disorders. It relates to the use of selected antihypertensive drugs and specific DPP-4 inhibitors or antidiabetic drugs which are pharmaceutically acceptable salts, hydrates or crystalline forms thereof. The medicament comprises a therapeutically or prophylactically effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The present invention is also selected from the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof for the manufacture of a medicament for the treatment, management or prevention of hypertension. The use of antihypertensive drugs with certain DPP-4 inhibitors or pharmaceutically acceptable salts, hydrates and crystalline forms thereof. The medicament comprises a therapeutically or prophylactically effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The present invention also relates to the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof for the manufacture of a medicament for the treatment, management or prevention of hypertension related disorders. It relates to the use of selected antihypertensive drugs and specific DPP-4 inhibitors or antidiabetic drugs which are pharmaceutically acceptable salts, hydrates or crystalline forms thereof. The medicament comprises a therapeutically or prophylactically effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The invention also selects from the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof for the manufacture of a medicament for the treatment, management or prevention of metabolic syndrome The use of antihypertensive drugs and specific DPP-4 inhibitors, or pharmaceutically acceptable salts, hydrates or crystalline forms thereof. The medicament comprises a therapeutically or prophylactically effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The present invention also provides an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt thereof, water for the manufacture of a medicament for treating, managing or preventing diabetes while reducing cardiac hypertrophy, particularly left ventricular hypertrophy It relates to the use of an antihypertensive agent selected from the group consisting of a hydrate or a crystalline form and a specific DPP-4 inhibitor or an antidiabetic agent which is a pharmaceutically acceptable salt, hydrate or crystalline form thereof. The medicament comprises a therapeutically or prophylactically effective amount of such an antihypertensive agent and an effective amount of such an antidiabetic agent in a combined or individual form.

  The present invention further provides a group consisting of an angiotensin II receptor antagonist and an ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof as a combined preparation for simultaneous, separate or sequential use in diabetes And a specific DPP-4 inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form of an antidiabetic agent.

  The present invention further provides an angiotensin II receptor antagonist and ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof as a combined formulation for simultaneous, separate or sequential use in diabetes related disorders. It relates to a medicament comprising an antihypertensive agent selected from the group consisting of and a specific DPP-4 inhibitor or an antidiabetic agent which is a pharmaceutically acceptable salt, hydrate or crystalline form thereof.

  The present invention further provides a group consisting of an angiotensin II receptor antagonist and an ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof as a combined preparation for simultaneous, separate or sequential use for hypertension And a specific DPP-4 inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form of an antidiabetic agent.

  The present invention further provides an angiotensin II receptor antagonist and an ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof as a combined preparation for simultaneous, separate or sequential use for hypertension related disorders. It relates to a medicament comprising an antihypertensive agent selected from the group consisting of and a specific DPP-4 inhibitor or an antidiabetic agent which is a pharmaceutically acceptable salt, hydrate or crystalline form thereof.

  The invention further comprises an angiotensin II receptor antagonist and an ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof as a combined preparation for simultaneous, separate or sequential use in metabolic syndrome It relates to a medicament comprising an antihypertensive agent selected from the group and a specific DPP-4 inhibitor or an antidiabetic agent which is a pharmaceutically acceptable salt, hydrate or crystalline form thereof.

  The present invention further provides an angiotensin II receptor antagonist and an ACE inhibitor or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in diabetes while reducing cardiac hypertrophy, particularly left ventricular hypertrophy, A pharmaceutical comprising an antihypertensive agent selected from the group consisting of hydrates or crystalline forms and a specific DPP-4 inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form of an antidiabetic agent About.

  The present invention further provides an antihypertensive agent selected from the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof and certain DPP-4 inhibitors or pharmaceutically It relates to a pharmaceutical composition containing an anti-diabetic agent in its acceptable salt, hydrate or crystalline form.

  The present invention further provides diabetes, hypertension-associated diabetes, diabetes-related disorders, hypertension by an individually administrable combination of an antihypertensive agent selected from angiotensin II receptor antagonists and ACE inhibitors and a specific DPP-4 inhibitor antidiabetic agent Or the treatment or prevention of hypertension related disorders. Thus, the present invention also relates to merging individual pharmaceutical compositions into one kit form. The kit of the present invention comprises two separate pharmaceutical compositions. The first unit dosage form comprises a prophylactically or therapeutically effective amount selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof. A hypotensive drug and a pharmaceutically acceptable carrier or diluent in a first unit dosage form, wherein the second unit dosage form comprises a prophylactically or therapeutically effective amount of a particular DPP-4 inhibitor or medicament. A pharmaceutically acceptable salt, hydrate or crystalline form thereof, and a pharmaceutically acceptable carrier or diluent in a second unit dosage form.

  The present invention also provides a prophylactically or therapeutically effective amount of an antihypertensive agent selected from the group consisting of angiotensin II receptor antagonists and ACE inhibitors or pharmaceutically acceptable salts, hydrates or crystalline forms thereof. At least one unit dose, and at the same time contains a prophylactically or therapeutically effective amount of a particular DPP-4 inhibitor or a pharmaceutically acceptable salt, hydrate or crystalline form thereof in at least one unit dose About the kit.

  In one embodiment of the invention, the kit further comprises a container. Such a kit is particularly suitable for delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a plurality of unit doses. Such a kit may include a card indicating the dosage of the appropriate dosage for the intended use. An example of such a kit is a “blister pack”. Blister packs are well known in the packaging industry and are widely used for packaging unit dosage forms. If desired, memory aids in the form of numbers, letters or other marks may be provided, or a calendar may be inserted to specify the date and time of drug administration in the treatment plan table.

Combination Therapy The composition of the present invention is useful for the treatment, prevention or management of diseases for which the compound included in the composition is used, such as diabetes, hypertension-related diabetes, diabetes-related disorders, hypertension, hypertension-related disorders. Can be used together. Such other agents may be administered simultaneously or sequentially with the compositions of this invention by their conventional routes and amounts. When a composition of the present invention is administered simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the composition of the present invention is preferred. However, combination therapy also includes therapies in which the composition of the invention and one or more other drugs are administered on different overlapping schedules. Also, when used in combination with one or more other active ingredients, it may be considered that the composition of the present invention and the other active ingredients are used in a smaller dose than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that comprise one or more other active ingredients in addition to the composition of the present invention.

  Non-limiting examples of other active ingredients that may be administered in individual forms in some cases and in combination with the compositions of the present invention as the same pharmaceutical composition are given below.

(A) Insulin sensitizers: (i) PPARγ agonists such as glitazones (eg troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, valaglitazone); other including PPARα / γ dual agonists PPAR ligands such as KRP-297, muraglitazar, nabeglitazar, tessaglitazar and TAK-559; PPARα agonists such as fenofibric acid derivatives (genfibrozil, clofibrate, fenofibrate and bezafibrate); selective PPARγ modulators (SPPARγMs) For example, WO 02/060388, WO 02/08188, WO 2004/018869, WO 2004/020409, WO 2004/020408 Those disclosed in finely WO 2004/066963; (ii) biguanides, such as metformin and phenformin, and, (iii) protein tyrosine phosphatase--1B (PTP-1B) inhibitors;
(B) insulin or insulin mimetics;
(C) sulfonylureas and other insulin secretagogues such as tolbutamide, glyburide, glipitide, glimepiride, and meglitinides such as nateglinide and repaglinide;
(D) α-glucosidase inhibitors (eg acarbose and miglitol);
(E) Glucagon receptor antagonists such as WO 97/16442, WO 98/04528, WO 98/21957, WO 98/22108, WO 98/22109, WO 99/01423, WO 00/39088 and WO 00/69810, Those disclosed in WO 2004/050039 and WO 2004/069158;
(F) GLP-1, GLP-1 analogs or mimetics, and GLP-1 receptor agonists such as exendin-4 (exenatide), liraglutide (NN-2211), CJC-1131, LY-307161, and WO Disclosed in 00/42026 and WO 00/59887;
(G) GIP and GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists;
(H) PACAP, PACAP mimetics and PACAP receptor agonists such as those disclosed in WO 01/23420;
(I) cholesterol-lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin and rosuvastatin and other statins), (ii) sequestering agents ( Colestyramine, colestipol and dialkylaminoalkyl derivatives of bridged dextran), (iii) nicotinyl alcohol, nicotinic acid or salts thereof, (iv) PPARα agonists such as fenofibric acid derivatives (genfibrozil, clofibrate, fenofibrate and Bezafibrate), (v) PPARα / γ dual agonists such as nabeglitazar and muraglitazar, (vi) cholesterol absorption in Bitter, for example, beta - sitosterol and ezetimibe, (vii) acyl CoA: cholesterol acyltransferase inhibitors such as avasimibe, and, (viii) anti-oxidants, e.g., probucol;
(J) PPARδ agonists, such as those disclosed in WO 97/28149,
(K) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonist, β3 adrenergic receptor agonist, melanocortin receptor agonist, in particular melanocortin-4 receptor agonist, Ghrelin antagonist, bombesin receptor agonist (eg, bombesin receptor subtype-3 agonist), cannabinoid CB1 receptor antagonist / inverse agonist, melanin-concentrating hormone (MCH) receptor antagonist;
(L) an ileal bile acid transporter inhibitor;
(M) drugs for inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, azulphidins and selective cyclooxygenase-2 (COX-2 inhibitors;
(N) Antihypertensive drugs, such as neutral endopeptidase inhibitors (eg thiorphan and phosphoramidon), aldosterone antagonists, renin inhibitors (eg, enalclein, RO42-5892, A65317, CP80794, ES1005, ES8891, SQ34017, Aliskiren, (2 (S), 4 (S), 5 (S), 7 (S) -N- (2-carbamoyl-2-methylpropyl) -5-amino-4-hydroxy-2,7-diisopropyl- 8- [4-methoxy-3- (3-methoxypropoxy) phenyl] -octanamide hemifumarate), SPP600, SPP630 and SPP635), endothelin receptor antagonists, vasodilators, calcium channel blockers (eg. , Amlodipine, Fedipine, verapamil, diltiazem, galopamil, nildipine, nimodipine, nicardipine), potassium channel activator (eg, nicorandil, pinacidil, cromakalim, minoxidil, apricalim, loprazolam), diuretic (eg, hydrochlorothiazide), sympathy Neuroleptics, beta-adrenergic blockers (eg, propranolol, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol tartrate), alpha adrenergic blockers (eg, doxazosin, prazosin or alphamethyldopa), central Alpha adrenergic agonist and peripheral vasodilator (eg hydralazine);
(O) Glucokinase activators (GKAs) such as those disclosed in WO 03/015774; WO 04/076420; and WO 04/081001;
(P) 11β hydroxysteroid dehydrogenase type 1 inhibitors, such as those disclosed in US Pat. Nos. 6,730,690; WO 03/104207; and WO 04/058741
(Q) an inhibitor of cholesteryl ester transfer protein (CETP), such as torcetrapib;
(R) inhibitors of fructose 1,6-bisphosphatase, such as disclosed in US Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476. Things.

  The above combinations include combinations of a composition of the present invention not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include a combination of a composition of the present invention and one or more active compounds selected from antidyslipidemic and antihypertensive agents. The combination of the composition of the present invention with one or more active compounds selected from antidyslipidemic and antihypertensive agents will be useful for the treatment, management or prevention of metabolic syndrome. A combination of a composition of the invention comprising a DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor, and an anti-dyslipidemic agent and / or other antihypertensive agent comprises: May be more effective in treating, managing or preventing metabolic syndrome than treatment with any of these drugs alone. In particular, a composition comprising an antihypertensive agent selected from the group consisting of a DPP-4 inhibitor, an angiotensin II receptor antagonist and an ACE inhibitor and an additional antihypertensive and / or antidyslipidemic agent is provided for the treatment, management of metabolic syndrome. Or it shows a synergistic effect on prevention.

Definitions The compounds in the compositions of the present invention include stereoisomers such as optical isomers and diastereomers depending on the mode of substitution. The compounds can contain one or more chiral centers and can be produced as racemates, racemic mixtures and individual diastereomers, enantiomeric mixtures or single enantiomers, and all isomeric forms are encompassed by the invention. The present invention includes all such isomeric forms of the compounds in the compositions of the present invention and mixtures thereof. Thus, when one compound is chiral, one enantiomer substantially free of the other enantiomer is included within the scope of the invention. Furthermore, all mixtures of both enantiomers are included. Also included within the scope of the invention are crystalline and hydrated forms, such as hydrates of the compounds of the invention.

  The single synthesis of these stereoisomers or their chromatographic separation may be performed by procedures known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing an asymmetric center of known absolute configuration, if necessary.

  If desired, racemic mixtures of the compounds can be separated and isolated into individual enantiomers. Separation involves the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into individual diastereomers by standard methods such as fractional crystallization or chromatography. It may be performed by a method known in the industry. Coupling reactions are often the formation of salts using enantiomerically pure acids or bases. The added chiral residue is then cleaved to convert the diastereomeric derivative to the pure enantiomer. Alternatively, a racemic mixture of compounds may be directly separated by a chromatographic method utilizing a chiral stationary phase. This method is well known in the art.

  Alternatively, one enantiomer of a compound may be produced by stereoselective synthesis methods known in the art using optically pure starting materials or reagents of known configuration.

  The present invention includes within its scope prodrugs of the compounds in the compositions of this invention. Prodrugs will generally be functional derivatives of the compounds in the composition that are readily converted into the required compounds in vivo. Accordingly, in the treatment methods of the present invention, the term “administering” is converted to a compound specifically disclosed as a component of the composition or a compound not specifically disclosed but specified in vivo after administration to a patient. Includes treatment of diabetes, hypertension-related diabetes, diabetes-related disorders, hypertension, hypertension-related disorders with compounds. Conventional procedures for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

  Some of the compounds described herein contain olefinic double bonds, and unless stated to the contrary, imply both E and Z geometric isomers.

  Some of the compounds described herein exist as tautomers with different hydrogen attachment points with one or more double bond shifts. For example, ketones and their enol forms are keto-enol tautomers. The individual tautomers and mixtures thereof are encompassed with the compounds of the invention.

  The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term “pharmaceutically acceptable salts” generally refer to non-toxic salts of the compounds of the invention prepared by reacting the free base with an appropriate organic or inorganic acid. To express. Representative salts of the basic compound of the present invention include, but are not limited to, acetate, benzensulfonate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, camsylate, carbonate , Chloride, clavulanate, citrate, edetate, edicylate, estrate, esylate, fumarate, glucoceptate, gluconate, glutamate, hexyl resorcinate, hydrobromide, hydrochloric acid Salt, hydroxy naphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, Mucoate, napsilate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate ), Palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, sebacate, succinate, tannate, tartrate, theocrate , Tosylate, triethyl iodide and valerate. Furthermore, when the compounds of the present invention contain an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, Includes salts derived from inorganic bases including manganous, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary and tertiary amines, salts of cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine. In, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine , Salts of methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

  A pharmaceutically acceptable salt of a composition of the invention is a composition in which one of the individual components of the composition is in the form of a pharmaceutically acceptable salt, or all of the individual components are pharmaceutically acceptable. A composition in the form of a salt (in which case the salts of each component may be the same or different), or a pharmaceutically acceptable salt of the combined ingredients (ie, a salt of the composition).

  As used herein, the term “composition” implies a product comprising a specified amount of a specified component in a specified amount, and a product obtained directly or indirectly from a combination of a specified amount of the specified component. Such terms are related to a pharmaceutical composition as a product comprising (one or more) active ingredient (s) and an inert ingredient (s) constituting the carrier, as well as a combination of two or more ingredients, It implies products obtained directly or indirectly from complexation or aggregation, or dissociation of one or more components, or other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier. The expression “pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. means.

Uses The compositions of the present invention are useful for the treatment or prevention of diabetes, particularly non-insulin dependent diabetes mellitus (NIDDM). In the text, diabetes does not matter whether the cause is hereditary or environmental.

  The composition of the present invention is useful for treating or preventing hypertension-associated diabetes. Hypertension-associated diabetes develops as a result of, or as a result of, hypertension, associated with hypertension.

  The compositions of the present invention are useful for the treatment or prevention of diabetes related disorders. Diabetes-related disorders in this text are associated with diabetes, develop due to or as a result of diabetes. Examples of diabetes related disorders are hyperglycemia, impaired glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, anti-LDL Levels, atherosclerosis and its sequelae, vascular recurrent stenosis, inflammatory bowel syndrome, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative diseases Retinopathy, neoplastic condition, adipocyte tumor, adipocyte cancer such as liposarcoma, prostate cancer, and other cancers such as gastric cancer, breast cancer, bladder cancer, colon cancer, angiogenesis, Alzheimer's disease, psoriasis, hypertension , Metabolic syndrome, ovarian androgen hyperplasia (polycystic ovary syndrome), and other disorders where insulin resistance is one of the components, such as sleep apnea. The composition of the present invention comprises hyperglycemia, impaired glucose tolerance, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, atherosclerosis and metabolic syndrome It is particularly useful for the treatment, management or prevention.

  The compositions of the present invention are also useful for the treatment or prevention of metabolic syndrome. The composition of the present invention further comprising an antihypertensive agent and / or an antidyslipidemic agent is useful for the treatment or prevention of metabolic syndrome.

  The composition of the present invention is useful for the treatment or prevention of diabetes.

  The compositions of the present invention are useful for the treatment, management or prevention of hypertension. Regardless of whether the cause of hypertension in the text is hereditary or environmental. A composition comprising a DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor also treats weight gain associated with certain antidiabetic drug treatments such as PPARγ agonists. And / or useful for prevention.

  The compositions of the present invention are useful for the treatment, management or prevention of hypertension related disorders. The hypertension-related disorders herein are associated with, caused by, or the result of hypertension. Examples of hypertension related disorders are hypertension, diabetes, high plasma insulin levels and insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, kidney cancer and colon cancer, osteoarthritis, obstruction Sleep apnea, gallstones, heart disease, abnormal heart rate and arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Freirich syndrome GH-deficient patients, normal mutant short stature, Turner syndrome, and reduced metabolic activity or of resting energy expenditure expressed as a percentage of total lean body mass such as, for example, children with acute lymphoblastic leukemia It is useful for the treatment, management and / or prevention of other pathological conditions that show a decrease.

  The term “diabetes” as used herein refers to insulin-dependent diabetes mellitus (ie, also known as IDDM, type 1 diabetes) and non-insulin-dependent diabetes mellitus (ie, also known as NIDDM, type 2 diabetes). Including both. Type 1 diabetes or insulin-dependent diabetes is the result of a lack of an absolute amount of insulin, a regulatory hormone for glucose utilization. Type 2 diabetes or non-insulin dependent diabetes mellitus (i.e., non-insulin dependent diabetes mellitus) often develops even when insulin is at normal or high levels, which is thought to be a result of the tissue failing to properly respond to insulin. The development of type 2 diabetes is related to hypertension. Most patients with type 2 diabetes are simultaneously obese. The compositions of the present invention are useful for the treatment of both type 1 diabetes and type 2 diabetes. The compositions of the present invention are particularly effective in the treatment of diabetes associated with hypertension. The term “diabetes associated with hypertension” refers to the condition of a diabetic patient in whom a hypertensive condition coexists. The composition is particularly effective in the treatment of type 2 diabetes. The compositions of the present invention are also useful for the treatment and / or prevention of gestational diabetes mellitus.

  Diabetes is characterized by fasting plasma glucose levels of 126 mg / dl or higher. In diabetic patients, fasting plasma glucose levels are 126 mg / dl. Characteristic of prediabetes is fasting plasma glucose (FPG) levels, impaired glucose tolerance or insulin resistance which has been increased from 110 mg / dl to 126 mg / dl. Pre-diabetic patients have an increased fasting glucose level (ie, a fasting plasma glucose (FGP) level greater than or equal to 110 mg / dl and less than 126 mg / dl) or impaired glucose tolerance (2 hour plasma glucose levels> 140 mg / dl < 200 mg / dl) or patients who show insulin resistance and consequently have a high risk of developing diabetes.

  Treatment of diabetes mellitus refers to the administration of the composition of the present invention to treat diabetic patients. One effect of treatment may be a reduction in glucose levels in patients with high glucose levels. Another effect of treatment would be a decrease in insulin levels in patients with high insulin levels. Another effect of treatment would be a reduction in plasma triglycerides in patients who exhibit high plasma triglycerides. Another effect of treatment would be a reduction in LDL cholesterol in patients with high LDL cholesterol levels. Another effect of treatment would be an increase in HDL cholesterol in patients with low HDL cholesterol levels. Another effect of treatment is an increase in insulin sensitivity. Another effect of treatment may be enhanced glucose tolerance in patients who have lost glucose tolerance. Another effect of treatment would be a decrease in insulin resistance in patients who have increased insulin resistance or who have high insulin levels. Prevention of diabetes mellitus, particularly diabetes associated with hypertension, means administration of a compound or combination of the present invention to prevent the development of diabetes in patients in need of prevention. Patients in need of diabetes prevention are pre-diabetic patients who are overweight or obese.

  As used herein, the term “hypertension” is used to identify essential or primary hypertension with no identified cause or more than one cause of hypertension, such as changes in both the heart and blood vessels, and the cause. Includes secondary hypertension. Causes of secondary hypertension include, but are not limited to, obesity, kidney disease, hormonal abnormalities, and the use of certain drugs such as oral contraceptives, corticosteroids, and cyclosporine. The term “hypertension” refers to blood pressure with high levels of both systolic and diastolic pressure (> 140 mmHg /> 90 mmHg), and systolic with a systolic pressure of 140 mmHg or more but a diastolic pressure of less than 90 mmHg. Including single hypertension. Normal blood pressure is defined as 120 mmHg (systolic pressure) or less and 80 mmHg (relaxation pressure) or more. A hypertensive patient is a patient who exhibits high blood pressure. A pre-hypertensive patient is a patient who exhibits a blood pressure between 120 mmHg / 80 mmHg and 139 mmHg / 89 mmHg. One effect of treatment is a reduction in blood pressure in hypertensive patients. Treatment of hypertension refers to administration of the combination of the present invention to treat hypertension in hypertensive patients. Prevention of hypertension refers to the administration of the combination of the invention to prevent the development of hypertension or hypertension related disorders in prehypertensive patients.

  Dyslipidemia or disorders of lipid metabolism are one or more lipids (ie cholesterol and triglycerides) and / or apolipoproteins (ie apolipoproteins A, B, C and E) and / or lipoproteins (ie LDL, It includes various conditions characterized by abnormal concentrations of lipids such as VLDL and IDL and polymer complexes formed by apolipoproteins that circulate lipids in the blood. Hyperlipidemia is associated with abnormally high levels of lipids, LDL and VLDL cholesterol and / or triglycerides. Treatment of dyslipidemia means administration of the combination of the invention to a patient with dyslipidemia. Prevention of dyslipidemia means administration of the combination of the invention to a pre-dyslipidemic patient. A pre-dyslipidemic patient is a patient who is not yet dyslipidemic but has a higher than normal lipid level.

  The term “Metabolic Syndrome” is used in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol III. E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359. In summary, individuals who exhibit more than two of abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, high fasting plasma glucose are defined as metabolic syndrome. These criteria are defined in ATP-III. Treatment of metabolic syndrome refers to administration of the combination of the invention to a patient with metabolic syndrome. Prevention of metabolic syndrome means administration of the combination of the invention to a patient with two disorders that define metabolic syndrome. A patient with two disorders defining metabolic syndrome is a patient who has developed two disorders that define metabolic syndrome but has not yet developed three or more disorders that define metabolic syndrome.

Left ventricular hypertrophy (LVH) is identified based on left ventricular mass index (LVMI) and relative wall pressure (RWT). The left ventricular mass index is defined as the left ventricular weight (g) divided by the body surface area (m ² ). Relative wall pressure is defined as 2 x posterior wall pressure / diastolic left ventricular end diameter. The normal value for LVMI is typically 85. The normal value of RWT is approximately 0.36. Male LVH patients have LVMI above 131 g / m ² and female LVH patients have LVMI above 100 g / m ² . Patients with high LVMI values, LVMI is male or LVMI from 85 g / ^{m 2} of 100 g / ^{m 2} Female 131 g / ^{m 2} from 85 g / ^{m 2.} Treatment of cardiac hypertrophy or left ventricular hypertrophy refers to administration of the combination of the present invention to a patient with cardiac hypertrophy or left ventricular hypertrophy. Prevention of cardiac hypertrophy or left ventricular hypertrophy means administration of a combination of the present invention for the purpose of reducing or maintaining LVMI in patients with high LVMI values or preventing LVMI elevation in patients with normal LVMI values.

  One effect of treating cardiac hypertrophy or left ventricular hypertrophy would be a decrease in ventricular weight. Another effect of treating cardiac hypertrophy or left ventricular hypertrophy may be a slowing of the rate of increase in ventricular weight. Another effect of treatment of cardiac hypertrophy or left ventricular hypertrophy may be a reduction in ventricular wall pressure. Another effect of treatment of cardiac hypertrophy or left ventricular hypertrophy may be a slowing rate of increase in ventricular wall pressure. One effect of treating diabetes while reducing cardiac hypertrophy or left ventricular hypertrophy would be a reduction in ventricular weight. Another effect of treating diabetes while reducing cardiac hypertrophy or left ventricular hypertrophy would be a slowing of the rate of increase in ventricular weight. Another effect of treating diabetes while reducing cardiac hypertrophy or left ventricular hypertrophy would be a reduction in left ventricular wall pressure. Another effect of treating diabetes while reducing cardiac hypertrophy or left ventricular hypertrophy would be a slowing of the rate of increase in left ventricular wall pressure.

As used herein, the term “obesity” is a condition in which there is excess body fat. The current definition of obesity is based on the body mass index (BMI) calculated as weight per square of height (kg / m ² ). “Obesity” is a condition in which an otherwise healthy patient has a body mass index (BMI) of 30 kg / m ² or higher, or a patient with at least one disease of 27 kg / m ² or higher. Represents the state of having a BMI. An “obese patient” is a patient who is otherwise healthy and has a BMI of 25 kg / m ² or more and less than 30 kg / m ² , or has at least one disease and has a BMI of 25 kg / m ² or more and less than 27 kg / m ² Represents patients.

Asians are at higher risk of developing obesity with a lower body mass index (BMI). In Asian countries, including Japan, “obesity” means that a patient with at least one obesity-induced or obesity-related comorbidity that requires or is improved by weight loss has a BMI of 25 kg / m ² or more. Indicates the state of possession. In Asian countries including Japan, “obese patients” have at least one obesity-induced or obesity-related disease that requires or is improved by weight loss and has a BMI of 25 kg / m ² or more Represents. In Asia Pacific countries, “obesity risk patients” are patients with a BMI of 23 kg / m ² or more and less than 25 kg / m ² .

  The term “obesity” as used herein includes all of the above definitions of obesity.

  Non-limiting examples of obesity-induced or obesity-related comorbidities include diabetes, non-insulin dependent diabetes mellitus (type 2), obesity-associated diabetes, impaired glucose tolerance, fasting glucose abnormalities, insulin resistance syndrome, dyslipidemia , High blood pressure, obesity-related hypertension, hyperuricemia, gout, coronary artery disease, myocardial infarction, unstable angina, sleep apnea syndrome, Picwick syndrome, fatty liver, cerebral infarction, cerebral thrombus, transient ischemic attack , Including musculoskeletal abnormalities, osteoarthritis, low back pain, menstrual abnormalities, infertility, lower back pain, increased anesthetic risk. Comorbidities include, among others, hypertension, hyperlipidemia, dyslipidemia, impaired glucose tolerance, cardiovascular disease, sleep apnea, diabetes mellitus and other obesity related conditions.

  In particular, the composition of the present invention is useful for the treatment of atherosclerosis. As used herein, the term “atherosclerosis” encompasses vascular diseases and conditions that are recognized and understood by physicians in the field of care. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vascular disease are all clinical manifestations of atherosclerosis and thus “athero” Included in the terms “atherosclerosis” and “atherosclerosis”. A composition of the invention comprising a therapeutically effective or prophylactically effective amount of a DPP-4 inhibitor in combination with a therapeutically effective or prophylactically effective amount of an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor It may be administered for the purpose of preventing or reducing the risk of recurrence when a congenital heart disease event, cerebrovascular event or intermittent claudication may occur or recur. Coronary heart disease events imply CHD death, myocardial infarction (ie, heart attack) and coronary revascularization procedures. A cerebrovascular event implies an ischemic or hemorrhagic stroke (also known as a cerebrovascular accident) and a transient ischemic stroke. Intermittent claudication is a clinical symptom of peripheral vascular disease. As used herein, the term “atherosclerotic disease event” implies coronary heart disease events, cerebrovascular events, and intermittent claudication. A person who has previously experienced one or more non-lethal atherosclerotic disease events falls under the possibility of a recurrence of such events.

  The term “administration” and / or “administering” the composition is to be understood to mean giving the composition of the invention to a patient in need of treatment. The pharmaceutical composition of the present invention comprises administration of a single pharmaceutical dosage form containing a DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor, and individual pharmaceutical dosage forms Includes administration of each active agent. When using individual dosage forms, the individual components of the composition may be administered at essentially the same time, i.e., simultaneously, or sequentially, i.e., sequentially before or after administration of the other component of the composition. It may be administered. Accordingly, the pharmaceutical compositions of the present invention encompass all such simultaneous or alternating treatment regimes, and the terms “administering” and “administering” should be understood accordingly. These various modes of administration would be appropriate for the compositions of the present invention so long as the beneficial pharmaceutical effect of the combination of antihypertensive and antidiabetic is exerted substantially simultaneously in the patient's body. Such beneficial effects are preferably obtained when the target blood level concentrations of each active agent are maintained substantially simultaneously. A combination of a DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor is preferably co-administered on a once daily dosing schedule, but the antihypertensive agent is administered once daily. Various dosage schedules, such as administering the antidiabetic drug once or more than once a day, are encompassed by the present invention. A single oral dosage form containing both drugs in combination is preferred. Single dosage forms provide convenience to the patient, and convenience considerations are particularly important for patients with diabetes, metabolic syndrome or obesity that require a large number of medications.

  As used herein, the term “patient” means a mammal, preferably a human, that is the subject of treatment, observation or testing. In one embodiment, the term “mammal” means “human” which is male or female. The combinations of the present invention are also useful for the treatment or prevention of feline and canine hypertension and hypertension related disorders. Thus, the term “mammal” includes companion animals such as cats and dogs.

  The term “patient in need” refers to a patient that a researcher, veterinarian, physician or other clinician has determined that treatment or prevention is necessary. In one embodiment, the patient in need thereof is a mammal. In another embodiment, the patient in need thereof is an obese patient. In another embodiment, the patient in need thereof is an obese patient with diabetes. In another embodiment, the patient in need thereof is an obese patient at risk for developing diabetes. In another embodiment, the patient in need thereof is a diabetic patient. In another embodiment, the patient in need thereof is an obese diabetic patient. In another embodiment, the patient in need thereof is a diabetic patient at risk for developing hypertension. In another embodiment, the patient in need thereof is an obese patient with metabolic syndrome. In another embodiment, the patient in need thereof is an obese patient at risk for developing metabolic syndrome. In another embodiment, the patient in need thereof is a diabetic patient with metabolic syndrome. In another embodiment, the patient in need thereof is a diabetic patient at risk for developing metabolic syndrome. In another embodiment, the patient in need thereof is an obese diabetic patient with metabolic syndrome. In another embodiment, the patient in need thereof is an obese patient at risk for developing metabolic syndrome. In another embodiment, the patient in need thereof is a diabetic patient at risk for developing metabolic syndrome. In another embodiment, the patient in need thereof is an obese diabetic patient at risk for developing metabolic syndrome.

  In another embodiment, the patient in need thereof is an obese patient with cardiac hypertrophy or left ventricular hypertrophy. In another embodiment, the patient in need thereof is a diabetic patient with cardiac hypertrophy or left ventricular hypertrophy. In another embodiment, the patient in need thereof is an obese diabetic patient with cardiac hypertrophy or left ventricular hypertrophy. In another embodiment, the patient in need thereof is an obese patient at risk of developing cardiac hypertrophy or left ventricular hypertrophy. In another embodiment, the patient in need thereof is a diabetic patient at risk for developing cardiac hypertrophy or left ventricular hypertrophy. In another embodiment, the patient in need thereof is an obese diabetic patient at risk for developing cardiac hypertrophy or left ventricular hypertrophy. In another embodiment, the patient in need thereof is an obese diabetic patient with cardiac hypertrophy or left ventricular hypertrophy being treated with a PPARγ agonist. In another embodiment, the patient in need thereof is an obese diabetic patient undergoing PPARγ treatment and at risk of developing cardiac hypertrophy or left ventricular hypertrophy.

  Administration of the compositions of the invention to practice the therapeutic methods of the invention is accomplished by administering a therapeutically or prophylactically effective amount of the compound in the composition to a patient in need of such treatment or prevention. The need for prophylactic administration according to the method of the invention is determined using known risk factors. The effective amount of an individual compound will ultimately be determined by the physician in charge of the case, but the exact name being treated, the severity of the disease and the other disease or condition the patient is suffering from, the route of choice, the patient It depends on a variety of factors, including other medications and treatments required at the same time, and other factors as determined by the physician.

  As used herein, the term “therapeutically effective amount” refers to a composition that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, patient or human body. Means the amount of active compound in it. This response includes alleviation of the symptoms of the disorder being treated. The novel treatment method of the present invention is a disorder treatment method known to those skilled in the art.

  The term “prophylactically effective amount” as used herein refers to a tissue, system, patient or human to prevent diabetes, hypertension-related diabetes, diabetes-related disorders, hypertension or hypertension-related diseases in patients at risk of developing the disorder. Means the amount of active compound in the composition that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician in the body.

  The value of the prophylactic or therapeutic dose of the active ingredient in the composition may vary with the severity of the condition to be treated, the particular compound in the composition and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for each compound in the combination ranges from about 0.0001 mg / kg to about 100 mg / kg, preferably from about 0.001 mg / kg to about 50 mg / kg of patient body weight. In a single dose or in divided doses. In some cases, it may be necessary to use dosages outside these ranges.

  When using an oral composition, an appropriate dosage range is, for example, from about 0.001 mg / kg to about 100 mg / kg, preferably from about 0.01 mg to about 2000 mg of each compound in the composition per day. Orally administered compositions may be from 0.01 mg to 1,000 mg, such as 0.01, 0.05, 0.1, 0.2, 0, so that the dosage to the patient being treated can be adjusted according to the symptoms. .5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850, 1 Preferably, it is provided in the form of a tablet containing 2,000 and 2,000 milligrams of each active ingredient. This dosage regimen will be adjusted to provide the optimal therapeutic response.

  The antidiabetic DPP-4 inhibitor in the composition of the present invention is administered at a daily dosage of about 0.1 mg / kg to about 100 mg / kg animal body weight in one or divided into 2 to 6 times or in sustained release form It is preferable to do this. For most large mammals, the total daily dosage is from about 1.0 mg to about 1000 mg, preferably from about 10 mg to about 200 mg. For a 70 kg adult, the total daily dose will generally be from about 7 mg to about 350 mg. This dosage regimen will be adjusted to provide the optimal therapeutic response.

  Dosage regimes using angiotensin II receptor antagonists or ACE inhibitors are based on patient type, species, age, weight, sex and medical condition, severity of condition being treated, route of administration, patient renal function and liver function. , Selected according to a variety of factors including the particular compound or salt thereof used. An average skilled physician or veterinarian can easily determine and prescribe the effective amount of drug needed to prevent, reverse or prevent the onset of a condition.

  For example, proper administration of an angiotensin II receptor antagonist can be accomplished by administering a commercially available concentration of a commercially available angiotensin II receptor antagonist, usually at a recommended dose. For example, losartan (25 to 100 mg once or twice daily using 25 or 50 mg active ingredient-containing dosage form); valsartan (80 to 160 mg once daily using active ingredient-containing dosage form) 320 mg); Irbesartan (75 to 300 mg once daily using 75, 150 or 300 mg active ingredient dosage form); Candesartan (4, 8, 16 or 32 mg active ingredient containing dosage form once daily Telmisartan (40-160 mg once daily using 40 or 80 mg of active ingredient-containing dosage form), and the like. Also, for example, proper administration of an ACE inhibitor can be performed by administering a commercially available concentration of a commercially available ACE inhibitor at a normally recommended dose. For example, benazepril (10-80 mg once daily with 5, 10, 20 or 40 mg active ingredient dosage form); captopril (12.5, 25 or 50 mg active ingredient containing dosage form with 1 day 2 to 3 times 25 to 50 mg); enalapril (5 to 40 mg once a day or 5 to 20 mg twice a day using 2.5, 5, 10 or 20 mg active ingredient dosage form); Fosinopril (10 to 40 mg per day using 10, 20 or 40 mg active ingredient dosage form); Lisinopril (2.5, 5, 10, 20, 30 or 40 mg active ingredient containing dosage form per day) 10-40 mg at a time; Moexipril (7.5-30 mg once or twice daily using 7.5 or 15 mg active ingredient containing dosage form); Perind Ril (4 to 16 mg once daily with 2, 4 or 8 mg active ingredient dosage form); quinapril (10 once daily with 5, 10, 20 or 40 mg active ingredient containing dosage form) Ramipril (2.5 mg or 2.5 to 20 mg in 1 or 2 divided doses using a 1.25, 2.5, 5 or 10 mg active ingredient dosage form); 1 to 4 mg once a day using 1, 2, or 4 mg active ingredient-containing dosage forms.

  The effective dosage of each active ingredient used in the composition may vary according to the particular compound used, the mode of administration, the condition being treated, the severity of the condition being treated. Accordingly, the dosage regimen using the composition of the present invention will include the patient type, species, age, general health, weight, diet, sex and medical condition, severity of the condition being treated, renal function of the patient and Selection is made according to a variety of factors including liver function, concomitant drugs, specific compounds used and their route of administration. An average skill physician, clinician or veterinarian can easily determine and prescribe the effective amount of drug needed to prevent, reverse or prevent the onset of a condition.

  The weight ratio of each agent in the combination of the invention will vary and will depend on the effective dose of each component. In general, each effective dose will be used.

  Another object of the present invention is to provide a pharmaceutical composition comprising each compound in the composition of the present invention together with a pharmaceutical carrier in a therapeutically or prophylactically effective amount. The term “composition”, such as a pharmaceutical composition, refers to an active ingredient (one or more) and an inactive ingredient (one or more) such as a pharmaceutically acceptable excipient that constitutes a carrier. Products containing, as well as combinations of two or more components, complexation or aggregation, or dissociation of one or more components, or another type of reaction or interaction of one or more components, directly or indirectly Implies the product obtained. Accordingly, the pharmaceutical composition of the present invention encompasses any composition produced by mixing an antihypertensive agent, an antidiabetic agent and a pharmaceutically acceptable excipient.

  Any suitable route of administration may be employed for providing an effective dosage of the composition of the present invention to a patient, particularly a human patient. For example, oral, rectal, external, parenteral, intraocular, intrapulmonary, intranasal, and the like can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like.

  The pharmaceutical composition of the present invention comprises, as an active ingredient, a combination of a DPP-4 inhibitor and an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor, or a pharmaceutically acceptable salt or ester thereof, In addition, it contains a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The expression “pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. means. The term “pharmaceutically acceptable salts” specifically refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

  The composition comprises compounds suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), intraocular (ophthalmic), pulmonary (aerosol inhalation) or intranasal administration, The optimal route for a given case will depend on the type and severity of the condition being treated and the type of active ingredient. These compositions will conveniently be prepared by any of the methods known in the pharmaceutical industry and provided as unit dosage forms.

  For inhalation administration, it is convenient to deliver the compositions of the invention in the form of an aerosol spray from a pressurized pack or nebulizer. The composition may also be delivered as a formulatable powder, and the powder composition may be inhaled with an aerated powder inhaler. Preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosols that can be formulated as suspensions or solutions of the present invention in suitable propellants such as fluorocarbons or hydrocarbons, or additional excipients added or not. A dry powder inhalation (DPI) aerosol that can be formulated as a dry powder of the composition upon addition.

  Suitable topical formulations for the compositions of the present invention include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, sprays, and the like. A topical pharmaceutical composition containing the composition of the present invention usually comprises about 0.005 to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal patches useful for administration of the compositions of the present invention include those known to the average person skilled in the art. To be administered in the form of a transdermal delivery system, of course, drug administration during the dosing schedule will be continuous rather than intermittent.

  The compositions of the invention can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, sterylamine or phosphatidylcholines.

  The compositions of the invention can also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are bound. The compounds in these compositions can also be bound to soluble polymers that serve as drug targeting carriers. Such polymers may include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl-methacrylamide phenol, polyhydroxyethyl asparamidophene, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compositions of the present invention are useful in class of biodegradable polymers useful for providing controlled release of drugs such as polyacetic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanos. It may be bonded to acrylate, hydrogel cross-linked or amphiphilic copolymers.

  The compositions of the invention can also be delivered as suppositories using bases such as cocoa butter, glycerinized gelatin, hydrogenated vegetable oils, and mixtures of polyethylene glycols of various molecular weights with fatty acid esters of polyethylene glycol.

  For practical use, each compound in the composition of the present invention is intimately mixed with a pharmaceutical carrier as an active ingredient according to a conventional pharmaceutical compounding technique. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). When preparing an oral dosage form composition, in the case of oral liquid preparations such as suspensions, elixirs and solutions, conventional pharmaceuticals such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. In the case of oral solid formulations such as powders, capsules, pellets, powders and tablets, where the vehicle is used, starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrant A carrier such as is used. Oral solid formulations are preferred over liquid formulations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

  In addition to the conventional dosage forms listed above, the compositions of the present invention are disclosed in U.S. Patents 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; Administration may be by controlled release means and / or delivery devices as described in US 4,008,719.

  Pharmaceutical compositions of the present invention suitable for oral administration are powders or powders each containing a predetermined amount of active ingredient, such as capsules (including timely or sustained release formulations), pills, cachets, powders, granules or tablets. May be provided as discrete units contained as granules, or aqueous liquids such as elixirs, tinctures, solutions, suspensions, syrups and emulsions, solutions or suspensions in non-aqueous liquids, oil-in-water types It may be provided as an emulsion or a water-in-oil liquid emulsion. Such compositions can be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the composition comprises uniformly and homogeneously mixing the active ingredient with a liquid carrier or finely divided solid carrier or both and then, if necessary, shaping the product to the desired appearance. For example, a tablet is prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are made by compressing in a suitable machine the active ingredients in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Can do. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert diluent.

  For example, for oral administration in the form of tablets, capsules, pellets or powders, the active ingredient may be a pharmaceutical such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium, etc. Combined with a pharmaceutically acceptable non-toxic oral inert carrier. For oral administration in liquid form, such as elixirs, syrups, slurries, emulsions, suspensions, solutions and foaming compositions, the oral pharmaceutical ingredients are pharmaceutically acceptable such as ethanol, glycerol, water, oil, etc. Combined with a non-toxic oral inert carrier. In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents, buffering agents, coatings and coloring agents can be added. Suitable binders include starch, gelatin, glucose, anhydrous lactose, free flowing lactose, natural sugars such as beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, guar gum, tragacanth gum or sodium alginate, Examples include carboxymethyl cellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. When the dosage unit form is a capsule, the capsule may contain a liquid carrier such as fatty oil in addition to the above types of materials.

  Desirably, each tablet contains 0.01 to 1,000 mg, particularly 0.01, 0.05, of each active ingredient in the composition of the invention so that the dosage for the patient to be treated can be adjusted according to the symptoms. 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225 , 250, 500, 750, 850 and 1,000 milligrams each of which is in a composition of the present invention so that the dosage for the patient being treated can be adjusted according to the symptoms. About 0.01 to 1,000 mg, especially 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20 25, 30, 40, 50, 75, 100, 125 It is contained in an amount of 150,175,200,225,250,500,750,850 and 000 milligrams.

  A representative example of the present invention is a pharmaceutical composition comprising a DPP-4 inhibitor as described above, an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an ACE inhibitor, and a pharmaceutically acceptable carrier. is there.

  Representative examples of the present invention also include combining any of the antihypertensive agents selected from the group consisting of a DPP-4 inhibitor and an angiotensin II receptor antagonist and an ACE inhibitor as described above with a pharmaceutically acceptable carrier. It is a prepared pharmaceutical composition. A representative of the present invention is a method for producing a pharmaceutical composition comprising the step of combining any of the above-mentioned antihypertensive and antidiabetic agents with a pharmaceutically acceptable carrier.

  The dosage regimen may be a single daily dose or may be administered in a daily dosage divided into 2 to 6 doses. Further, based on the characteristics of the individual compounds selected for administration, it may be used less frequently, for example once a week, twice a week, once a month. In the case of low dosing frequency, the unit dosage will of course be increased accordingly.

  Of course, when administered as an intranasal route, transdermal route, rectal or vaginal suppository, or as a continuous intravenous solution, drug administration during the dosing regimen will be continuous rather than intermittent.

The following is an example of a representative pharmaceutical dosage form of the composition of the present invention.
Tablet 190mg / tablet Losartan potassium 50mg
Sitagliptin phosphate * 64.25mg
Microcrystalline cellulose 53.19mg
Hydroxypropylcellulose 9mg
Croscarmellose sodium 9mg
Magnesium stearate 4.5mg
Butylated hydroxyanisole (BHA) 0.06mg
64.25 mg dihydrogen phosphate is equivalent to 50 mg free base.

The manufacturing method direct compression method includes the following steps:
(1) Blend losartan potassium, sitagliptin phosphate and croscarmellose sodium in a V-blender or other suitable blender for about 5 to 30 minutes;
(2) Add hydroxypropyl cellulose and microcrystalline cellulose to improve compression properties;
(3) Lubricate with magnesium stearate for about 1 to 15 minutes;
(4) compress the lubricated blend into the desired tablet form; and, if desired,
(5) Film coating.

Antioxidants such as BHA or BHT may be layered on one of the excipients before mixing with losartan potassium and sitagliptin phosphate or other excipients, or during the bulk drug synthesis process It may be added by overlaying potassium and sitagliptin phosphate. Optionally tablets, standard HPC / HPMC / TiO ₂ film of 6.00 mg - the coated tablets of 156mg coated with coating formulation ^(Opadry I ^(R)).

  The range of compositions of the compounds of the present invention in combination with other agents useful for treating or preventing hypertension and hypertension-related conditions in principle includes any combination with any composition useful for the treatment of hypertension and hypertension-related disorders. It will be understood to do.

  A DPP-4 inhibitor comprising a compound of structural formula IV for use in the compositions of the present invention was prepared as described in US Pat. No. 6,699,871. The entire contents of this patent are incorporated into the present invention by reference. The dihydrogen phosphate salt of structural formula V and its crystalline monohydrate form were prepared by the procedure described below.

(2R) 4-Oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl] -1- (2,4,5-trifluorophenyl) butan-2-amine dihydrogen phosphate monohydrate (sitagliptin phosphate monohydrate)
Production of 3- (trifluoromethyl) -5,6,7,8-tetrahydro [1,2,4] triazolo [4,3-α] pyrazine hydrochloride (1-4)

Step A : Preparation of bishydrazide (1-1) Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added in 60 minutes. The internal temperature rose from 14 ° C to 25 ° C. The resulting solution was aged at 22-25 ° C. for 60 minutes. The solution was cooled to 7 ° C. At a temperature of 16 ° C. or lower, 17.9 g of 50 wt% NaOH aqueous solution (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously in 130 minutes. When the reaction was complete, the mixture was vacuum distilled at 27-30 ° C. under 26-27 Hg vacuum to remove water and ethanol. During the distillation, 720 mL of acetonitrile was added slowly to maintain a constant volume (about 500 mL). The slurry was filtered to remove sodium chloride. The cake was washed with about 100 mL of acetonitrile. Removal of the solvent gave bis-hydrazide 1-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 4.2 (s, 2H), 10.7 (s, 1H), 11.6 (s, 1H) ppm.
¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ 41.0, 116.1 (q, J = 362 Hz), 155.8 (q, J = 50 Hz), 165.4 ppm.

Step B : Preparation of 5- (trifluoromethyl) 2- (chloromethyl) -1,3,4-oxadiazole (1-2) Step A bishydrazide 1-1 (43.) in ACN (82 mL). 2 g, 0.21 mol) was cooled to 5 ° C. Phosphorus oxychloride (32.2 g, 0.21 mol) was added while maintaining the temperature below 10 ° C. The mixture was heated to 80 ° C. and aged at this temperature for 24 hours until HPLC showed 1-1 less than 2 area%. In a separate container, 260 mL of IPAc and 250 mL of water were mixed and cooled to 0 ° C. The reaction slurry was charged to the quench while maintaining the internal temperature below 10 ° C. After the addition, the mixture was stirred vigorously for 30 minutes and the aqueous layer was removed when the temperature rose to room temperature. The organic layer was then washed with 215 mL water, 215 mL 5 wt% aqueous sodium bicarbonate, and finally 215 mL 20 wt% aqueous brine. The HPLC assay yield after treatment was 86-92%. Removal of the volatiles by distillation at 75-80 mm Hg, 55 ° C. gave an oil that was used directly in Step C without further purification. Alternatively, the product may be purified by distillation to 1-2 .

¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.8 (s, 2H) ppm.
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 32.1, 115.8 (q, J = 337 Hz), 156.2 (q, J = 50 Hz), 164.4 ppm.

Step C : Preparation of N-[(2Z) -piperazine-2-ylidene] trifluoroacetohydrazide (1-3) -Ethylenediamine (33.1 g, 0.55 mol) in methanol (150 mL) cooled to 20 ° C. To the solution was added Stage B distilled oxadiazole 1-2 (29.8 g, 0.16 mol) while maintaining an internal temperature of -20 ° C. After completion of the addition, the resulting slurry was aged at −20 ° C. for 1 hour. Ethanol (225 mL) was then charged and the slurry was slowly warmed to -5 ° C. After maintaining at −5 ° C. for 60 minutes, the slurry was filtered and washed with −5 ° C. ethanol (60 mL). Amidine 1-3 was obtained as a white solid (24.4 g, 99.5 area wt% pure by HPLC).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 2.9 (t, 2H), 3.2 (t, 2H), 3.6 (s, 2H), 8.3 (b, 1H) ppm.
¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ 40.8, 42.0, 43.3, 119.3 (q, J = 350 Hz), 154.2, 156.2 (q, J = 38 Hz) ppm.

Step D : Preparation of 3- (trifluoromethyl) -5,6,7,8-tetrahydro [1,2,4] triazolo [4,3-α] pyrazine hydrochloride (1-4) in 110 mL of methanol A suspension of amidine 1-3 (27.3 g, 0.13 mol) was heated to 55 ° C. At this temperature, 37% hydrochloric acid (11.2 mL, 0.14 mol) was added in 15 minutes. During the addition, the solid completely dissolved and a clear solution was obtained. The reaction mixture was aged for 30 minutes. The solution was cooled to 20 ° C. and aged at this temperature until a seed bed was formed (10 minutes to 1 hour). 300 mL of MTBE was charged at 20 ° C. over 1 hour. The resulting slurry was cooled to 2 ° C., aged for 30 minutes and filtered. The solid was washed with 50 mL ethanol: MTBE (1: 3) and dried at 45 ° C. under vacuum.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 3.6 (t, 2H), 4.4 (t, 2H), 4.6 (s, 2H), 10.6 (b, 2H) ppm.
¹³ C-NMR (100 MHz, DMSO-d ₆ ): δ 39.4, 39.6, 41.0, 118.6 (q, J = 325 Hz), 142.9 (q, J = 50 Hz), 148.8 ppm.

Step A : 4-Oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl] -1- Preparation of (2,4,5-trifluorophenyl) butan-2-one (2-3) 2,4,5-trifluorophenylacetic acid ( 2-1 ) (150 g, 0.789 mol), Meldrum acid (125 g , 0.868 mol) and 4- (dimethylamino) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-necked flask. Room temperature N, N-dimethylacetamide (DMAc) (525 mL) was added in one portion to dissolve the solid. Room temperature N, N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion while maintaining the temperature below 40 ° C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 hours while maintaining the temperature at 0 to 5 ° C. The reaction mixture was aged at 5 ° C. for 1 hour. Triazole hydrochloride 1-4 (180 g, 0.789 mol) at 40-50 ° C. was added in one portion. The reaction solution was aged at 70 ° C. for several hours. Next, 5% aqueous sodium hydrogen carbonate solution (625 mL) was added dropwise at 20-45 ° C. The batch was seeded and aged at 20-30 ° C. for 1-2 hours. 525 mL of 5% aqueous sodium hydrogen carbonate solution was added dropwise over 2-3 hours. After aging for several hours at room temperature, the slurry was cooled to 0-5 ° C. and aged for 1 hour, after which the solid was filtered. The wet cake was washed with 20% DMAc aqueous solution (300 mL), then twice with an additional 20% DMAc aqueous solution (400 mL) and finally with water (400 mL). The cake was sucked dry at room temperature.

Step B : (2Z) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl ] Preparation of 1- (2,4,5-trifluorophenyl) but-2-en-2-amine (2-4) Methanol (100 mL), ketoamide 2-3 (200 g) in a 5 L round bottom flask And charged with ammonium acetate (110.4 g). Next, methanol (180 mL) and 28% aqueous ammonium hydroxide solution (58.6 mL) were added while maintaining the temperature during addition at 30 ° C. or lower. An additional amount of methanol (100 mL) was added to the reaction mixture. The mixture was heated to reflux temperature and aged for 2 hours. The reaction mixture was cooled to room temperature and then cooled to about 5 ° C. with an ice bath. After 30 minutes, the solid was filtered and dried to give 2-4 as a solid. m. p. 271.2 ° C.

Step C : (2R) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl Preparation of 1- (2,4,5-trifluorophenyl) butan-2-amine (2-5) Chloro (1,5-cyclooctadiene) rhodium (I) dimer {[Rh (Cod) Cl] ₂ } (292 mg, 1.18 mmol) and (R, S) t-butyl Josiphos (708 mg, 1.3 mmol) were charged under a nitrogen atmosphere. Then degassed MeOH (200 mL) was added and the mixture was stirred at room temperature for 1 h. A 4 L hydrogenator was charged with enamine amide 2-4 (118 g, 0.29 mol) along with MeOH (1 L). The slurry was degassed. The catalyst solution was then transferred to a hydrogenator under nitrogen. After degassing three times, the enamine amide was hydrogenated at 50 ° C. under 200 psi hydrogen gas for 13 hours. The assay yield determined by HPLC was 93% and the optical purity was 94% ee.

The optical purity was further improved by the following procedure. The methanol solution after hydrogenation reaction (18 g in 180 mL MeOH) was concentrated and replaced with methyl t-butyl ether (MTBE) (45 mL). To this solution was added aqueous H ₃ PO ₄ (0.5 M, 95 mL). After layer separation, 3N NaOH (35 mL) was added to the aqueous layer and then extracted with MTBE (180 mL + 100 mL). The MTBE solution was concentrated and the solvent was replaced with hot toluene (180 mL, ca. 75 ° C.). The hot toluene solution was then allowed to cool slowly to 0 ° C. (5-10 hours). Crystals were isolated by filtration (13 g, 72% yield, 98-99% ee); m. p. 114.1-115.7 ° C.

¹ H-NMR (300 MHz, CD ₃ CN): δ 7.26 (m), 7.08 (m), 4.90 (s), 4.89 (s), 4.14 (m), 3.95 (M), 3.40 (m), 2.68 (m), 2.49 (m), 1.40 (bs).

Compound 2-5 exists as an amide bond rotamer. Without the annotation, the carbon-13 signal is not fully resolved, so the majority and minority rotamers are combined.

¹³ C-NMR (CD ₃ CN): δ 171.8, 157.4 (ddd, J _CF = 242.4, 9.2, 2.5 Hz), 152.2 (major), 151.8 (minor), _{149.3 (ddd; J CF = 246.7,14.2,12.9Hz} ), 147.4 (ddd, J CF = 241.2,12.3,3.7Hz), 144.2 (q, _{J CF = 38.8Hz), 124.6 (} ddd, J CF = 18.5,5.9,4.0Hz), 120.4 (dd, J CF = 19.1,6.2Hz), 119. 8 (q, J _CF = 268.9 Hz), 106.2 (dd, J _CF = 29.5, 20.9 Hz), 50.1, 44.8, 44.3 (minor), 43.2 (minor) ), 42.4, 41.6 (minor), 41.4, 39.6, 8.5 (minor), 36.9.

Crystalline free base can also be isolated by the following procedure:
(A) Charge the reaction mixture, which has completed the hydrogenation stage, with 25 wt% Ecosorb C-941. The mixture is stirred for 1 hour under nitrogen and then filtered. The cake is washed with 2 L / kg methanol. The recovery rate of free base is about 95% and the optical purity is about 95% ee.
(B) Concentrate the solution of the free base in methanol to a volume of 3.5-4.0 L / kg (based on free base charge), then replace the solvent with isopropanol (IPA) to a final volume of 3.0 L / kg. .
(C) The slurry is heated to 40 ° C., aged at 40 ° C. for 1 hour, and then cooled to 25 ° C. in 2 hours.
(D) Charge heptane (7 L / kg) in 7 hours and stir the slurry at 22-25 ° C. for 12 hours. The supernatant concentration before filtration is 10-12 mg / g.
(E) Filter the slurry and wash the solid with 30% IPA / heptane (2 L / kg).
(F) The solid is dried in a vacuum oven at 40 ° C.
(G) The optical purity of the free base is about 99% ee.

(2R) -4-oxo-4- [3- (trifluoromethyl-5,6-dihydroxy [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl-1- ( 2,4,5-trifluorophenyl) butan-2-amine dihydrogen phosphate monohydrate (sitagliptin phosphate monohydrate)
To a 250 mL round bottom flask equipped with an overhead stirrer, heating mantle and thermocouple, 31.5 mL isopropanol (IPA), 13.5 mL water, 15.0 g (36.9 mmol) (2R) -4- Oxo-4- [3- (trifluoromethyl) -5,6-dihydro [l, 2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl] -1- (2,4 5-Trifluorophenyl) butan-2-amine free base and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid solution were charged. The mixture was heated to 75 ° C. A viscous white precipitate was formed at low temperature but dissolved when 75 ° C was reached. The solution was cooled to 68 ° C. and maintained at this temperature for 2 hours. A solid slurry bed was formed during this aging time [the solution can be seeded with a monohydrate of 0.5 to 5 wt% small particle size (alpine milling)]. The slurry was then cooled to 21 ° C. at a rate of 4 ° C./hour and maintained overnight. Then 105 mL of IPA was added to the slurry. After 1 hour, the slurry was filtered and washed with 45 mL of IPA (solids could also be washed with water / IPA solution to avoid conversion to other crystalline forms), then the solids were dried on an open frit. 18.6 g of solid was recovered. According to HPLC area percentage (HPLC conditions are the same as above), the solid was more than 99.8% pure. Particle size distribution analysis of the isolated solids showed an average PSD of 80 microns and 180 microns of less than 95%. X-ray powder diffraction and thermogravimetric analysis showed that the solid crystalline form was a monohydrate.

DPP-4 inhibitor (sitagliptin phosphate) and losartan potassium combination therapy test in humans (effects on hypertension and glucose / insulin)
Materials and methods :
A suitable number of BMI ≧ 30 indicating a fasting plasma glucose level decrease, glucose intolerance or high serum insulin indicative of pre-diabetic insulin resistance status or high serum glucose level indicative of type II diabetes Advise subjects on diet and increased physical activity. After a 2-week placebo treatment period that includes a standardized program of diet, physical activity, and lifestyle change, patients were randomly divided into 4 treatment groups, each with a placebo, effective daily dose, eg, 100 mg sitagliptin phosphate. An effective daily dose such as 50 mg losartan potassium, an effective dose such as 50 mg losartan potassium and an effective dose such as 100 mg sitagliptin phosphate are administered. Losartan potassium is administered once a day or more, which has been determined to be effective. Sitagliptin phosphate is administered in a dosage regimen that has been determined to be effective once or more times a day. The two compounds may be administered in a combined dosage form. Patients are treated for 6 months and blood pressure is measured periodically to determine the therapeutic effect on blood pressure. Serum glucose and insulin levels are measured on the first day (day 0), then every 4 to 12 weeks, and after the last dose.

  An effective combination reduces blood pressure, improves serum insulin levels that are indicative of improved insulin sensitivity, and / or reduces fasting glucose levels.

Non-diabetic rodent model of metabolic syndrome: Trial of combination therapy with DPP-4 inhibitor (sitagliptin phosphate) and losartan potassium (effect on blood pressure and serum insulin)
The following experiment demonstrates the ability of the composition to reduce blood pressure in an animal model of metabolic syndrome. This experiment uses a non-diabetic rodent model in which blood insulin levels and blood pressure are high, but serum glucose levels are in the normal range.

Materials and Methods Male Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) with an initial weight of 175-199 g are used for all experiments. All rats are fed Purina Rat Chow (no. 5012; St. Louis, MO) and are allowed to drink water ad libitum under a 12 hour (0600-1800 hour) light / dark cycle prior to feeding. Rats are then fed a diet (TD78463; Harlan Teklad, Madison, Wis.) That provides 60% of the total calories as fructose. The fructose enriched diet is continued for 11 days, during which time the rats are habituated to the blood pressure measurement procedure. The ambient temperature is maintained at 30 ° C. The equipment used was a manual scanner (Model 65-12, ETC, Inc., Woodland Hills, CA), a pulse amplifier (Model 59, ETC, Inc.) and a dual channel recorder (Model 1202, Linear Intrs. Corp., Reno). , Nevada) is a magnetic animal holder.

  After the end of the initial diet period, blood pressure is measured and the rats are randomly divided into two groups. Both groups continue on a fructose-enriched diet, but one group is gavaged with sitagliptin phosphate (eg, 100 mpk PO) and losartan potassium, and the other group is treated similarly with vehicle alone. Blood pressure is measured weekly before and after administration of the combination or vehicle (8 weeks of treatment). The overall procedure for both is the same. At 0900, rats are removed from the animal room and placed in the laboratory. Leave water in a quiet environment until you measure your blood pressure at 1300 hours. Systolic blood pressure is measured using a tail-cuff method without external preheating. Systolic blood pressure was measured consciously, and the value measured with this technique was found to be the same as that obtained by direct intraarterial cannulation. Final blood pressure measurements were made in the afternoon of the day of the last combination or vehicle administration. Tail venous blood is collected from approximately half of the test rats at 1300 hours (4 hours after food removal), centrifuged and frozen before assaying for plasma glucose and insulin. Plasma free fatty acid concentrations are enzymatically assayed by the ACS-ACOD method using a commercial kit (Waro Chemicals Inc., Richmond, Va.).

  The animal model used in this example has many features of metabolic syndrome. Fructose fed rats do not show an increase in blood glucose, so this is not a diabetes model. However, these rats show increased serum insulin, increased triglyceride and free fatty acid levels, and increased blood pressure. Therefore, this animal model is an animal model of metabolic syndrome.

  An effective composition ameliorates a series of characteristic symptoms associated with metabolic syndrome. Effective compositions improve at least two of the symptoms of metabolic syndrome, ie blood pressure, blood insulin, free fatty acids, body weight and triglyceride levels, in a non-diabetic rat model with normal blood glucose levels.

In addition, animal models such as BRS3 KO mice (Ohki-Hamazki et al., Nature , 390: 165 (1997)) and diet-induced obese hypertensive dogs (Hall et al., Am. J. Hypertension , 14: 103S-115S (2001)) are also available. Can be used.

  Although the invention has been described and illustrated based on some specific embodiments, various applications, changes, modifications, replacements, deletions or additions of procedures and protocols are possible without departing from the spirit and scope of the invention. Those skilled in the art will appreciate this. For example, effective dosages other than the specific dosages described hereinabove may be used depending on the reactivity of the mammal being treated with any of the compound formulations of the invention set forth above. The specific pharmacological response observed depends on or depending on the specific active compound selected, or depending on whether a pharmaceutical carrier is present, or depending on the type of formulation and the mode of administration used. However, it is believed that such variations or differences in expected results will be suitable for the purposes and practice of the present invention. Accordingly, the invention is defined by the following claims, which are to be construed as broadly as possible.

Claims (11)

(A) an antihypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme (ACE) inhibitor; and (b) a structural formula:

(2R) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H) -yl]- A dipeptidyl peptidase-4 inhibitor which is 1- (2,4,5-trifluorophenyl) butan-2-amine or a pharmaceutically acceptable salt, hydrate and crystalline form thereof;
A pharmaceutical composition comprising The pharmaceutically acceptable salt of the dipeptidyl peptidase-4 inhibitor has the structural formula:

The pharmaceutical composition according to claim 1, which is dihydrogen phosphate or pharmaceutically acceptable hydrate thereof.   The angiotensin II receptor antagonist according to claim 2, selected from the group consisting of losartan, candesartan, irbesartan, valsartan, telmisartan and eprosartan or a pharmaceutically acceptable salt, hydrate or crystalline form thereof. Pharmaceutical composition.   ACE inhibitors are alacepril, benazepril, captopril, celonapril, cilazapril, delapril, enalapril, enalaprilate, fosinopril, imidapril, lisinopril, mobiletipril, moexipril, perindopril, quinapril, spirapril, spirapril 3. A pharmaceutical composition according to claim 2 selected from the group consisting of its salts, hydrates or crystalline forms thereof.   The pharmaceutical composition according to claim 2, wherein the dihydrogen phosphate salt is in the form of crystalline monohydrate.   A method of treating a condition selected from hypertension, diabetes, diabetes-related disorders, hypertension and hypertension-related disorders, comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim 2.   The method of claim 6, wherein the dihydrogen phosphate salt is in the form of crystalline monohydrate.   The method of claim 6, wherein the diabetes is type 2 diabetes.   The method of claim 6, wherein the condition is hypertension.   The diabetes-related disorders include hyperglycemia, pre-diabetes, impaired glucose tolerance, decreased fasting glucose, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL level, high 7. The method of claim 6, selected from the group consisting of LDL levels, atherosclerosis, hypertension, sleep apnea, polycystic ovary syndrome and metabolic syndrome.   Use of a composition according to claim 2 in a therapeutically effective amount for the manufacture of a medicament useful for the treatment of hypertension, diabetes, diabetes related disorders, hypertension and hypertension related disorders in patients in need of treatment.